Gene targeted drugs are designed with oligonucleotides of nucleobase sequence of 10-20 units, complementary to the regulatory region of the disease associated target gene. Upon administration, they bind to specific promoter targets (DNA) and block access to RNA polymerase and as a consequence, no mRNA or the corresponding gene products are produced (Agarwal, S. in Applied antisense oligonucleotide technology, Stein, C. A. & Kreig, A. M. Ed., 1978, Wiley-Liss Inc). Depending on the target chosen, the drugs can be developed for application as antiviral, anticancer agents or other instances where conventional drugs have serious limitations. They are also useful for research and in diagnostics for detection and isolation of specific nucleic acids. Since natural oligonucleotides are degraded by nucleases, there is considerable interest in synthetic analogues of oligonucleotides that are stable under physiological conditions (Uhlmann, E. and Peyman, A. Chem. Rev. 1990, 90, 543; Leyten, I., Herdewijn, P., Eur. J. Chem., 1998, 33, 515). In order to achieve this, a large number of variations in polynucleotide backbones have been undertaken, although so far not with the desired results. The great majority of these backbone modifications led to decreased stability for hybrids formed between the modified oligonucleotide and its complementary natural oligonucleotide, except in the case of aminoethylglycyl peptide nucleic acids (aegPNA I) (Nielsen, P. E. et al Science 1991, 254, 1497).

In these compounds, a linear amide chain composed of repeating aminoethylglycine units to which nucleobase ligands are attached replaces the cyclic sugar-phosphate backbone of DNA and are amenable for easy preparation by solid phase peptide synthesis. PNAs can be used to target ss or ds DNA to produce gene regulatory molecules and as hybridization probes. Polypyrimidine PNAs form triple helices with ds DNA and are useful as antigene agents. Triplex formation and strand displacement are the only known principles in the art for sequence-specific recognition of ds DNA, with strand displacement being superior to the former. This is because unlike triplex formation, it is not restricted to homopurine-homopyrimidine sequences and allows the recognition of any sequence by Watson-Crick base pairing of the four natural nucleobases. The strand invasion of double strand DNA by unmodified PNAs is only possible in the absence of salts or at ionic strengths much lower than the physiological conditions. (Hyrup, B. and Nielsen P. E., BioMed. Chem. Lett. 1996, 4, 5).
The PNA molecules although make stable hybrids with complementary DNA, are poorly soluble in aqueous media and being non-chiral bind to complementary DNA in both parallel and antiparallel directions whenever the sequence permits (Hanvey, J. C. et al Science 1992, 258, 1481; Uhlmann, E. et al Angew. Chem. Int. Ed Engl. 1998, 37, 2796). Several structural variations within such a PNA backbone have been sought, in order to improve the water solubility, orientation specificity and DNA double strand invasion at physiological conditions, without compromising on the DNA affinity and sequence specificity. Typically, these involve conjugation with positively charged ligands such as lysine (Kim, S. H. et al J. Am. Chem. Soc. 1993, 115, 6477; Koch, T. et al Tetrahedron Lett. 1995, 36, 6933; Ishihara, T. and Corey, D. R. J. Am. Chem. Soc. 1999, 121, 2012) and introduction of substituents in the ethylenediamine or glycine sectors of the backbone. (Haaima, G. et al Angew. Chem. Int. Ed. Engl. 1996, 35, 1939; Gangamani, B. P. et al Tetrahedron 1999, 55, 177; D'Costa, M. et al Organic Lett. 1999, 1, 1513.). However, it is well understood in the art of the PNA backbone modifications that no PNA analogs have yet emerged where these problems have been simultaneously and satisfactorily addressed (Ganesh and Nielsen, Curr. Organic Chemistry, 2000, 9, 916). The following relevant patents on PNA so far are cited here.
PatentNo.AuthorsTitle1WOHarriot, P.; Nelson,New cell permeable signal peptides9964449J.; Wallace, A.useful for intracellular deliveryof molecules2WOLowe, G.New proline based chiral peptide9816550nucleic acid compounds-havingstrong hybridisation activity,useful as antisense, antigene agentsor in molecular biology3WODemidov, V. V.;Nucleic acid clamp comprising two9714793Frank-Kamenetskii,sequences of peptide nucleicM. D.; Veselkov,acids-connected by flexible linkerA. G.with stabilizer at ends, used e.g., tocleave target nucleic acid4WOBuchardt, O.;New peptide nucleic acid9620212Lagriffoul, P.;monomers with chiral backbone-Nielsen, P. E.may be used in preparation ofoligomers useful e.g., as researchtools